JP2021522308A - 上皮細胞及び骨髄細胞の両方を活性化するtlr3リガンド - Google Patents
上皮細胞及び骨髄細胞の両方を活性化するtlr3リガンド Download PDFInfo
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Abstract
Description
(I) [P]a[Q]b[R]c
(式中、
− Qは、A又はUのホモポリマーを表し、bは、少なくとも15、20、25、30、35、40、45、50、60、70、80、90、又はそれ以上の整数であり;そのようなブロックは、任意に、A(Q=Aの場合)/U(Q=Aの場合)、G、I及びCの中で20、15、14、13、12、11、10、9、8、7、6、5、4、3、2、1%未満の他の塩基を含み得る;
− a、b及びcは、塩基又はヌクレオチドの数を表すため、a+b+cは、鎖又はdsRNAの長さを表す;
− a及びcは、独立して、0又はa+b+c=50〜200、好ましくは60〜120、より好ましくは70〜100の間のような整数であり得る;a、b及びcは、同一又は異なる場合がある;
− a=1ならば、Q=Aの場合において、Pは、U、G、I及びCのうち1つの塩基から構成され;相補性の結果、Q=Uの場合において、Pは、A、G、I及びCのうち1つの塩基から構成される;
− a>1ならば、Pは、次の何れかの構成で、A、U、G、I及びCのうち少なくとも1つ又は2つの塩基から構成される:これらの塩基の少なくとも2つのランダムな組み合わせ、A、U、G、I及びCの中の塩基の1つのブロック、A、U、G、I及びCの中の異なる塩基の少なくとも2つのブロック、又はA、U、G、I及びCの中の塩基の少なくとも1つのブロック及びA、U、G、I及びC中の少なくとも1つの他の塩基の混合物;
− c=1ならば、R=Aの場合において、Rは、U、G、I及びCの中の1つの塩基で構成され;相補性の結果、R=Uの場合において、Pは、A、G、I及びCの中の塩基の1つで構成される;
− c>1ならば、Rは、次の何れかの構成で、A、U、G、I及びC中の少なくとも1つ又は2つの塩基で構成される:これらの塩基の少なくとも2つのランダムな組み合わせ、A、U、G、I及びCの中の塩基の1つのブロック、A、U、G、I及びCの中の異なる塩基の少なくとも2つのブロック、又はA、U、G、I及びCの中の塩基の少なくとも1つのブロック及びA、U、G、I及びC中の少なくとも1つの他の塩基の混合物;
− P及びRは、塩基及び/又は配列の長さに関して同一又は異なる場合がある。)
[A]b
[U]b
[P]a[A]b[R]c
[Y]a[U]b[Z]c
b=20、25又は30〜100、特に約35〜約100、特に約40〜約100、最良では約50〜約100、例えば、約50〜約90、好ましくは約50〜約80、例えば、約40、約50、約60、約70、約80の整数であり、
a及びcは、独立して約10〜約50、好ましくは約15〜約40である。
b=10、15、20、25又は30〜100、特に約35〜約100、特に約40〜約100、最良では約50〜約100、例えば、約50〜約90、好ましくは約50〜約80、例えば、約40、約50、約60、約70、約80の整数であり、
a及びcは、独立して約5〜約50、好ましくは約15〜約50であり、好ましくは約15〜約40である。
b=は、10〜100の間の整数であり、
a及びcは独立して約10〜約50、好ましくは約15〜約40である。
b=10、15、20、25又は30〜100の間の整数、特に約35〜約100、特に約40〜約100、最良では約50〜約100、例えば、約50〜約90、好ましくは約50〜約80、例えば、約40、約50、約60、約70、約80であり、
a及びcは、独立して約10〜約50である。
[A]b[R]c
[U]b[Z]c
b=20、25又は30〜100の間の整数、特に約35〜約100、特に約40〜約100、最良では約50〜約100、例えば、約50〜約90、好ましくは約50〜約80、例えば、約40、約50、約60、約70、約80であり、
c=約10〜約50、好ましくは約15〜約40、好ましくは約30〜約40、例えば約35、約40、約45である。
b=10、15、20、25又は30〜100の間の整数、特に約35〜約100、特に約40〜約100、最良では約50〜約100、例えば、約50〜約90、好ましくは約50〜約80、例えば、約40、約50、約60、約70、約80であり、
c=約10〜約50、好ましくは約15〜約40、好ましくは約30〜約40、例えば約35、約40、約45である。
b=10〜100の間の整数、又は約35〜約100であり、
c=約30〜約50、好ましくは約30〜約40、例えば約35、約40、約45である。
b=10、15、20、25又は30〜100の間の整数、特に約35〜約100、特に約40〜約100、最良では約50〜約100、例えば、約50〜約90、好ましくは約50〜約80、例えば、約40、約50、約60、約70、約80であり、
c=約10〜約50である。
[P]a[A]b
[Y]a[U]b
b=20、25又は30〜100の間の整数、特に約35〜約100、特に約40〜約100、最良では約50〜約100、例えば、約50〜約90、好ましくは約50〜約80、例えば、約40、約50、約60、約70、約80であり、
a=約10〜約50、好ましくは約15〜約40、好ましくは約30〜約40、例えば約35、約40、約45である。
b=10〜100の間の整数、特に約35〜約100、特に約40〜約100、最良では約50〜約100、例えば、約50〜約90、好ましくは約50〜約80、例えば、約40、約50、約60、約70、約80であり、
a=約10〜約50、好ましくは約15〜約40、好ましくは約30〜約40、例えば約35、約40、約45である。
b=10〜100の間の整数、特に約35〜約100であり、
a=約30〜約50、好ましくは約30〜約40、例えば約35、約40、約45である。
b=10〜100の間の整数、特に約35〜約100、特に約40〜約100、最良では約50〜約100、例えば、約50〜約90、好ましくは約50〜約80、例えば、約40、約50、約60、約70、約80であり、
a=約10〜約50である。
[P]a[A]b[R]c
[Y]a[U]b[Z]c
b=約20、25又は30〜約100の間の整数であり、a又はcのいずれかが0であり、a及びcが同時に0に等しくない場合、約10〜約50である。
本発明者達は、様々な塩基組成、二本鎖上のヌクレオチドの分布、及びRAWマウスマクロファージ細胞系統によるTNF−アルファ産生を誘発する能力を有する配列を有する一連の合成dsRNAをスクリーニングした。試験した最初の47個のdsRNAを表1に示す。市販のポリ(A:U)及びネイティブアクリルアミドゲルで9個の345、397、398、415、418、405、411、412、413配列の分析は、異なる長さのdsRNAの混合物である市販のポリ(A:U)とは対照的に、単一の主要なバンドが、各合成50bp dsRNAの予想サイズで検出可能であることを示す(図1)。47個の合成dsRNAをマウスマクロファージRaw細胞によるTNF−アルファの産生を活性化する能力についてテストした際、効果的なものは確認できなかったが、市販の高分子量ポリ(A:U)と同じくらい効果的な50bpのポリ(A:U)配列(以下、配列412と称する)が確認された。従って、配列412は、マクロファージによって効率的に内在化され、TLR3の下流のNF−Kbシグナル伝達経路を誘発することが可能である。注目すべきは、50bpのポリ(A:U)のAs及びUsが二本鎖上で分布されている場合(配列413)、TNF−アルファの分泌は、観察されなかった。意外なことに、50bpのポリ(I:C)(配列411)は、TNF−アルファの産生を誘発することができなかった。
5’(I)10−(U)50−(I)10 3’
5’(A)60−(I)10 3’
5’(A)50−(I)20 3’
5’(A)20−(I)50 3’
5’(I)5−(A)60−(I)5 3’
5’(I)15−(A)40−(I)15 3’
5’(I)20−(A)30−(I)20 3’
5’(I)25−(A)20−(I)25 3’
5’(I)5−(A)50−(I)15 3’
5’(I)13−(A)64−(I)13 3’
5’(I)10−(A)70−(I)10 3’
5’(A)10−(I)60 3’
5’(I)30−(A)10−(I)30 3’
互換的に使用される「TLR3」、「TLR3タンパク質」、及び「TLR3受容体」は、本明細書において、トール(Toll)様受容体(TLR)ファミリーのメンバーであるトール様受容体3を指すために使用される。そのアミノ酸配列は、NCBI遺伝子ID7098に示される。トール様受容体3は、病原体の認識及び自然免疫の活性化の基本的な役割を担うトール様受容体(TLR)ファミリーのメンバーである。この受容体は、胎盤及び膵臓で最も豊富に発現しており、白血球の樹状細胞亜集団に限定される。ウイルス感染に関するdsRNAを認識し、NF−kBの活性化及びI型インターフェロンの産生を誘導する。
TLR3アゴニストとは、本明細書において、別段の定めが無い限り、本発明によるdsRNAを意味する。
本明細書に記載のTLR3アゴニストによる治療は、任意に、癌の治療に有用な1つ以上の他の治療薬と有利に組み合わせられ得る。従って、本明細書に記載のTLR3アゴニストは、癌の治療に有用な他の治療薬と一緒に、又は組み合わせて使用され得る。従って、TLR3アゴニスト組成物は、癌の治療に有用な他の治療薬を含み得る。他の治療薬は、同じ又は好ましくは別の容器に入っていてもよい。そのような薬剤には、異なるヌクレオチド配列の他のdsRNA−TLR3アゴニスト;限定されないが、細胞毒性及び殺腫瘍性TLR3リガンド複合体で使用するために上記に記載されたものを含む細胞毒素;細胞毒性及び殺腫瘍性TLR3リガンド複合体;腫瘍抗原又は腫瘍増殖性タンパク質を標的とする薬剤;限定されないが、シスプラチン(CDDP)、カルボプラチン、オキサリプラチン、プロカルバジン、メクロレタミン、シクロフォスファミド、カンプトテシン、イホスファミド、メルファラン、クロラムブシル、ブスルファン、ニトロスレア、ダクチノマイシン、ダウノルビシン、ドキソルビシン、ブレオマイシン、プリコマイシン、マイトマイシン、エトポシド(VP16)、タノキシフェン、ラロキシフェン、エストロゲン受容体結合剤、タキソール、ゲムシタビン、ナベルビン、ファメシルタンパク質タンスフェラーゼ阻害剤、トランスプラチナ、5−フルオロウラシル、ビンクリスチン、ビンブラスチン及びメトトレキサート、又は前述の何れかの類似体又は誘導変異体を含む化学療法剤;例えば乳癌の場合:ドキソルビシン、エピルビシン、ドキソルビシンとシクロフォスファミド(AC)の組み合わせ、シクロフォスファミド、ドキソルビシン及び5−フルオロウラシル(espaceajoute)(CAF)の組み合わせ、シクロフォスファミド、エピルビシン及び5−フルオロウラシル(CEF)、ハーセプチン(商標)の組み合わせ、タモキシフェン、タモキシフェンと細胞毒素の組み合わせ、ドセタキセルとパクリタキセルを含むタキサン、タキサンとドキソルビシン及びシクロフォスファミドの組み合わせ;結腸癌の場合:5−FUとロイコボリンの組み合わせ、5−FUとレバミゾールの組み合わせ、又はイリノテカン、5−FUとロイコボリン(IFL)又はオキサリプラチンの組み合わせ;前立腺癌の場合:放射性同位元素(すなわち、パラジウム、ストロンジウム−89及びイリジウム)、ロイプロリド又は他のLHRアゴニスト、非ステロイド系抗アンドロゲン(フルタミド、ニルタミド、及びビカルタミド)、ステロイド系抗アンドロゲン(酢酸シプロテロン)、ロイプロリドとフルタニドの組み合わせ、DES等のエストロゲン、クロロトリアニセン、エチニルエストラジオール、抱合型エストロゲンU.S.P.、DES−二リン酸、アミノグルテチミド、ヒドロコルチゾン、フルタミド休薬、プロゲステロン、及びケトコナゾール等の第2選択ホルモン療法、又はドセタキセル、パクリタキセル、エストラムスチン/ドセタキセル、エストラムスチン/エトポシド、エストラムスチン/ビンブラスチン、及びエストラムスチン/パクリタキセルを含む症状の自覚的改善及びPSA値の低下をもたらすと報告されている他の化学療法剤又はその併用剤;メラノーマの場合:ダカルバジン(DTIC)、カルムスチン(BCNU)及びロムスチン(CCNU)等のニトロソウレア、ビンカアルカロイド、プラチナ化合物、及びタキサンなどの適度な単剤活性を有する薬剤、ダートマスレジメン(シスプラチン、BCNU、及びDTIC)、インターフェロンアルファ(IFN−A)、及びインターロイキン−2(IL−2);卵巣癌の場合:パクリタキセル、ドセタキセル、シスプラチン、オキサリプラチン、ヘキサメチルメラミン、タモキシフェン、イホスファミド、パクリタキセル(タキソール)又はドセタキセル(タキソテール)とシスプラチン又はカルボプラチンの組み合わせ、シクロフォスファミドとシスプラチンの組み合わせ、シクロフォスファミドとカルボプラチンの組み合わせ、5−フルオロウラシル(5−FU)とロイコボリン、エトポシド、リポソームドキソルビシン、ゲルシタビン又はトポテカンの組み合わせ;肺癌の場合:シスプラチン、ビンクリスチン、ビンブラスチン、マイトマイシン、ドキソルビシン、及びエトポシドの単独又は組み合わせ、シクロフォスファミド、ドキソルビシン、ビンクリスチン/エトポシド、及びシスプラチン(CAV/EP)の組み合わせ、シスプラチンとビノレルビン、パクリタキセル、ドセタキセル又はゲムシタビンの組み合わせ、及びカルボプラチンとパクリタキセルの組み合わせ等の特定の癌の治療のための治療薬及び治療薬の組み合わせを含む。
本明細書は、癌又はその1つ以上の症状の予防、管理、治療又は回復に使用するためのTLR3アゴニストを包含する。本発明はまた、癌又はその1つ以上の症状の予防、管理、治療又は回復のための薬剤の製造のためのTLR3アゴニストの使用を包含する。また、癌又はその1つ以上の症状の予防、管理、治療、又は回復するための方法も包含する。
様々な実施形態において、本明細書は、癌の対象の治療レジメンを決定するための方法を提供する。当該方法は、何れかの癌、又は腫瘍の治療レジメンを決定するために使用され得、例えば、悪性腫瘍及び関連疾患には、以下のものに限定されないが、TLR3を発現するものを含む。
標準的な合成方法を使用して、本発明の明細書に従ってdsRNA組成物が産生され得る。一例として、標準的なホスホルアミダイト固相合成技術が使用され得る(参照、M. D. Matteucci et al., Tetrahedron Lett. 22, 1859-1862 (1981))。2’−ACE RNA合成化学が用いられ得、これはS.A. Scaringeによる博士学位論文、コロラド大学1996年に開示される保護基スキームに基づく。GE Healthcare社のRNAi、遺伝子発現&遺伝子編集、2’−ACE RNA合成化学のためのDharmacon(商標)テクノロジーが使用され得る。実施例で使用されるアクリルアミドゲル等のゲルでの電気泳動等の方法を使用して、純度を確認することができる。
TLR3:トール様レセプター3(Toll−like Receptor 3)(CD283)
WT:野生型(Wild Type)
KO:ノックアウト(Knock Out)
TBE:トリスホウ酸塩EDTA(Tris Borate EDTA)
APS:過硫酸アンモニウム(Ammonium Persulfate)
TEMED:テトラメチルエチレンジアミン(Tetramethylethylenediamine)
BET:ブロムレエチジウム(Bromure Ethidium)
DNA:デオキシリボ核酸(Deoxyribonucleic Acid)
RNA:リボ核酸(Ribonucleic Acid)
dsRNA:二本鎖RNA(double stranded RNA)
ssRNA:一本鎖RNA(single stranded RNA)
Poly(A:U):ポリアデニル酸ポリウリジル酸(PolyAdenylic PolyUridylic acid)
PAU:高分子量の市販のポリ(A:U)(high molecular weight commercial Poly(A:U))
Poly(I:C):ポリイノシン酸ポリシチジル酸(PolyInosinic PolyCytidylic acid)
PIC:ポリ(I:C)(Poly(I:C))
bp:塩基対(base pair)
mTNFa:マウス腫瘍壊死因子アルファ(mouse Tumor Necrosis Factor alpha)
hIL6:ヒトインターロイキン−6(human Interleukin−6)
Å:オングストローム(Angstrom)
5’ppp:5’三リン酸(5’tri−phosphate)
ISRE:インターフェロン刺激応答要素(Interferon Stimulated Response Element)
5’(I)10−(U)50−(I)10 3’
5’(A)60−(I)10 3’
5’(A)50−(I)20 3’
5’(A)20−(I)50 3’
5’(A)10−(I)60 3’
5’(I)5−(A)60−(I)5 3’
5’(I)15−(A)40−(I)15 3’
5’(I)20−(A)30−(I)20 3’
5’(I)25−(A)20−(I)25 3’
5’(I)30−(A)10−(I)30 3’
5’(I)5−(A)50−(I)15 3’
5’(I)13−(A)64−(I)13 3’
5’(I)10−(A)70−(I)10 3’
Claims (14)
- 2本の相補鎖を有するdsRNAから本質的になる二本鎖RNA(dsRNA)を含む組成物であって、ポリAの少なくとも1つのブロック又はホモポリマーと、ポリUの相補的ブロック又はホモポリマーを含み、各ブロックが、少なくとも15、20、25又は30のA、又はUを含み、及び各鎖が、50〜200塩基の間、好ましくは55〜200塩基の間の定められた長さを有し、及び医薬的に許容されるビヒクル、担体又は賦形剤を含む、組成物。
- 前記dsRNAが、下記の式(I):
(I)[P]a[Q]b[R]c
(式中、
− Qは、A又はUのホモポリマーを表し、bは、少なくとも15、20、25、30、35、40、45、50、60、70、80、90以上の整数を表し;
− a及びcは、独立して0又はa+b+c=50〜200、好ましくは60〜120、より好ましくは70〜100の間であるような整数であってもよく;a、b及びcは、等しくても異なっていてもよく;
− a=1ならば、Q=Aの場合、Pが、U、G、I及びCのうちの1つの基から作られ;Q=Uの場合、Pが、A、G、I及びCのうちの1つの基から作られ;
− a>1ならば、以下の何れかの構成で、Pが、A、U、G、I及びCのうちの少なくとも1つ又は2つの塩基から作られる:これらの塩基の少なくとも2つの組み合わせ、A、U、G、I及びCのうちの塩基の1つのブロック、A、U、G、I及びCのうちの異なる塩基の少なくとも2つのブロック、又はA、U、G、I及びCのうちの少なくとも1つのブロック並びにA、U、G、I及びCのうちの少なくとも1つの他の塩基の混合物;
− c=1ならば、R=Aの場合、Rは、U、G、I及びCのうちの1つの塩基で作られ、
− c>1ならば、Rは、以下の何れかの構成で、A、U、G、I、及びCのうちの少なくとも1つ又は2つの塩基で作られる:これらの塩基の少なくとも2つのランダムな組み合わせ、A、U、G、I及びCのうちの塩基の1つのブロック、A、U、G、I及びCのうちの異なる塩基の少なくとも2つのブロック、又はA、U、G、I及びCのうちの塩基の少なくとも1つのブロック並びにA、U、G、I及びCのうちの少なくとも1つの他の塩基の混合物;
− P及びRは、塩基及び/又は配列の長さに関して同一又は異なる場合がある)
によるAの少なくとも1つのブロックを有し、ここで、前記dsRNAが、少なくとも20%、好ましくは少なくとも25%、より好ましくは少なくとも50%、さらに好ましくは少なくとも70%のA及びUを含む、請求項1に記載の組成物。 - 前記dsRNAが、式(II):
[A]b
[U]b
(式中、
b=50〜200、最良では約55〜約100、150又は200、好ましくは、約60〜約120、好ましくは約70〜約100の間、例えば、約60、約70、約80、約90である)
である、請求項1又は2に記載の組成物。 - 前記dsRNAが、式(III):
[P]a[A]b[R]c
[Y]a[U]b[Z]c
(式中、
P及びRが、G、I及び/又はCの中から選択され、並びにY及びZは、相補的な塩基である。
特に、
b=20、25又は30〜100の間、特に約35〜約100、特に約40〜約100、最良では約50〜約100、例えば、約50〜約90、好ましくは約50〜約80、例えば、約40、約50、約60、約70、約80の整数であり、
a及びcが、独立して、約10〜約50、好ましくは約15〜約40である。)
である、請求項1又は2に記載の組成物。 - 前記dsRNAが、式(IV):
[A]b[R]c
[U]b[Z]c
(式中、
Rが、G、I及び/又はCの中から選択され、Zが、相補的な塩基である。
特に、
b=20、25又は30〜100の間、特に約35〜約100、特に約40〜約100、最良では約50〜約100、例えば、約50〜約90、好ましくは約50〜約80、例えば、約40、約50、約60、約70、約80の整数であり、
c=約10〜約50、好ましくは約15〜約40、好ましくは約30〜約40、例えば、約35、約40、約45である)
である、請求項1又は2に記載の組成物。 - 前記dsRNAが、式(V):
[P]a[A]b
[Y]a[U]b
(式中、
Pが、G、I及び/又はCの中から選択され、Yが、相補的な塩基である。
特に、
b=20、25又は30〜100、特に約35〜約100、特に約40〜約100、最良では約50〜約100、例えば、約50〜約90、好ましくは約50〜約80、例えば、約40、約50、約60、約70、約80の整数であり、
a=約10〜約50、好ましくは約15〜約40、好ましくは約30〜約40、例えば、約35、約40、約45である。)
である、請求項1又は2に記載の組成物。 - 前記dsRNAが、式(VI):
[P]a[A]b[R]c
[Y]a[U]b[Z]c
(式中、
P及びRが、I及びCの中から独立して選択され、並びにY及びZが、相補的な塩基であり、
b=約20、25又は30〜約100の間の整数であり、
a又はcのうちの1つが、0であり得、並びにa及びcが、同時に0に等しくない場合、約10〜約50である。)
である、請求項1又は2に記載の組成物。 - 前記Aのブロックが、20、15、14、13、12、11、10、9、8、7、6、5、4、3、2、1%未満のU、G、I及びCのうちの他の塩基を含む、請求項1〜7の何れか1項に記載の組成物。
- 組成物1ml当たり0.01〜100mgの前記dsRNAを含む、請求項1〜8の何れか1項に記載の組成物。
- 医薬としての、請求項1〜9の何れか1項に記載の組成物。
- TLR3受容体を発現する癌を治療する方法で使用するための請求項1〜9の何れか1項に記載の組成物。
- 前記組成物が、骨髄細胞を活性化し、上皮癌細胞の死を誘発する、請求項11に記載の使用のための組成物。
- 前記組成物が、骨髄細胞によって発現されるTLR3を活性化し、炎症性サイトカイン及びケモカインの分泌を誘導し、ヒト又は哺乳動物の癌細胞における炎症及び死のTLR3依存性活性化を誘発する、請求項11に記載の使用のための組成物。
- 前記組成物及び化学療法薬が、哺乳動物又はヒトへの同時、別個、又は連続投与用である、請求項11〜13の何れか1項に記載の使用のための組成物。
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EP3788147A1 (en) * | 2018-05-04 | 2021-03-10 | Tollys | Tlr3 ligands that activate both epithelial and myeloid cells |
US11813279B2 (en) * | 2018-12-21 | 2023-11-14 | Aim Immunotech Inc. | Compositions for cancer therapy and methods |
WO2022189861A1 (en) | 2021-03-08 | 2022-09-15 | Tollys | Carbohydrate conjugates of tlr3 ligands and uses thereof |
WO2022229302A1 (en) | 2021-04-28 | 2022-11-03 | Enyo Pharma | Strong potentiation of tlr3 agonists effects using fxr agonists as a combined treatment |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006054177A1 (en) * | 2004-11-19 | 2006-05-26 | Institut Gustave Roussy | Improved treatment of cancer using tlr3 agonists |
Family Cites Families (31)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US353072A (en) | 1886-11-23 | Fence-clamp | ||
US4369172A (en) | 1981-12-18 | 1983-01-18 | Forest Laboratories Inc. | Prolonged release therapeutic compositions based on hydroxypropylmethylcellulose |
DE3583799D1 (de) | 1985-01-11 | 1991-09-19 | Abbott Lab Ltd | Feste zubereitung mit langsamer freisetzung. |
US5665710A (en) | 1990-04-30 | 1997-09-09 | Georgetown University | Method of making liposomal oligodeoxynucleotide compositions |
JP2773959B2 (ja) | 1990-07-10 | 1998-07-09 | 信越化学工業株式会社 | 大腸内放出性固形製剤 |
JP3220180B2 (ja) | 1991-05-23 | 2001-10-22 | 三菱化学株式会社 | 薬剤含有タンパク質結合リポソーム |
US5756122A (en) | 1995-06-07 | 1998-05-26 | Georgetown University | Liposomally encapsulated nucleic acids having high entrapment efficiencies, method of manufacturer and use thereof for transfection of targeted cells |
US6750044B1 (en) | 1996-10-17 | 2004-06-15 | Genentech, Inc. | Variants of vascular endothelial cell growth factor having antagonistic properties, nucleic acids encoding the same and host cells comprising those nucleic acids |
UA73092C2 (uk) | 1998-07-17 | 2005-06-15 | Брістол-Майерс Сквібб Компані | Таблетка з ентеросолюбільним покриттям і спосіб її приготування |
EP1101490B1 (en) | 1998-07-28 | 2005-04-13 | Tanabe Seiyaku Co., Ltd. | Preparation capable of releasing drug at target site in intestine |
US7521068B2 (en) | 1998-11-12 | 2009-04-21 | Elan Pharma International Ltd. | Dry powder aerosols of nanoparticulate drugs |
KR100816572B1 (ko) | 1999-04-28 | 2008-03-24 | 보드 오브 리전츠, 더 유니버시티 오브 텍사스 시스템 | 항-vegf 항체 및 이를 포함하는 약제학적 조성물 |
US6461631B1 (en) | 1999-11-16 | 2002-10-08 | Atrix Laboratories, Inc. | Biodegradable polymer composition |
GB0119346D0 (en) * | 2001-08-08 | 2001-10-03 | Bioclones Proprietary Ltd | Process for the maturation of dendritic cells |
US6800663B2 (en) | 2002-10-18 | 2004-10-05 | Alkermes Controlled Therapeutics Inc. Ii, | Crosslinked hydrogel copolymers |
KR101339628B1 (ko) | 2005-05-09 | 2013-12-09 | 메다렉스, 인코포레이티드 | 예정 사멸 인자 1(pd-1)에 대한 인간 모노클로날 항체, 및 항-pd-1 항체를 단독 사용하거나 기타 면역 요법제와 병용한 암 치료 방법 |
DK1907424T3 (en) | 2005-07-01 | 2015-11-09 | Squibb & Sons Llc | HUMAN MONOCLONAL ANTIBODIES TO PROGRAMMED death ligand 1 (PD-L1) |
US20090041809A1 (en) * | 2007-03-07 | 2009-02-12 | Nventa Biopharmaceuticals Corporation | Double-stranded locked nucleic acid compositions |
WO2009014708A2 (en) | 2007-07-23 | 2009-01-29 | Cell Genesys, Inc. | Pd-1 antibodies in combination with a cytokine-secreting cell and methods of use thereof |
RU2531758C2 (ru) | 2008-02-11 | 2014-10-27 | Куретек Лтд. | Моноклональные антитела для лечения опухолей |
US8168757B2 (en) | 2008-03-12 | 2012-05-01 | Merck Sharp & Dohme Corp. | PD-1 binding proteins |
EP2281043B1 (en) | 2008-04-25 | 2013-03-13 | Innate Pharma | Improved tlr3 agonist compositions |
CN114835812A (zh) | 2008-12-09 | 2022-08-02 | 霍夫曼-拉罗奇有限公司 | 抗-pd-l1抗体及它们用于增强t细胞功能的用途 |
HUE049647T2 (hu) | 2009-11-24 | 2020-09-28 | Medimmune Ltd | Targetált kötõdõ ágensek B7-H1 ellen |
WO2012088272A1 (en) * | 2010-12-21 | 2012-06-28 | Duke University | Methods and compositions combining immunotherapy with monocyte activation |
RU2625034C2 (ru) | 2011-04-20 | 2017-07-11 | МЕДИММЬЮН, ЭлЭлСи | Антитела и другие молекулы, которые связывают в7-н1 и pd-1 |
KR20190133790A (ko) | 2011-08-01 | 2019-12-03 | 제넨테크, 인크. | Pd-1 축 결합 길항제 및 mek 억제제를 사용하는 암 치료 방법 |
JP6502959B2 (ja) | 2013-12-12 | 2019-04-17 | 上海恒瑞医薬有限公司 | Pd−1抗体、その抗原結合性断片及びそれらの医学的使用 |
WO2015091578A1 (en) * | 2013-12-16 | 2015-06-25 | Riboxx Gmbh | Double-stranded polyc:poly(g/i) rna for immunostimulation and cancer treatment |
GB201711379D0 (en) * | 2017-07-14 | 2017-08-30 | Univ Cape Town | Maturation of dendritic cells |
EP3788147A1 (en) * | 2018-05-04 | 2021-03-10 | Tollys | Tlr3 ligands that activate both epithelial and myeloid cells |
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Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006054177A1 (en) * | 2004-11-19 | 2006-05-26 | Institut Gustave Roussy | Improved treatment of cancer using tlr3 agonists |
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